Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries (PAs), characterized by an increase in PA pressure and vascular remodeling leading to a progressive increase in pulmonary vascular resistance (Rich et al., 1987). The consequence of vascular obliteration is right heart failure and high mortality (Jeffery et al., 2002; Voelkel et al., 1997). Germline mutations in the gene coding for the bone morphogenetic protein (BMP) type-2 receptor (BMPR2), a receptor for the transforming growth factor (TGF)-β super-family, have been identified in approximately 70% of patients with the heritable form of PAH (hPAH) (Morrell et al., 2001). Moreover, BMPR2 expression is also markedly reduced in PAH cases in the absence of mutations in this gene (idiopathic PAH, iPAH), suggesting a broader role for this receptor pathway in the development of PAH. In pulmonary artery smooth muscle cells (PASMCs) mutations in BMPR2 are associated with an abnormal growth response to BMPs and TGF-β. In endothelial cells, these mutations increase the susceptibility of cells to apoptosis (PAECs) (Morrell et al., 2001). The absence of BMPR2 mutations in some families and in the majority of iPAH cases suggests that further pathological mechanisms, possibly related to the TGF-β super-family, still need to be identified.
One of the main histopathological features common to all forms of PAH is the accumulation of cells expressing smooth muscle specific α-actin (SMA) in peripheral pulmonary arteries. This includes the appearance of SMA-positive cells in the neointima and the extension of SMA-positive cells into precapillary pulmonary arterioles that are normally devoid of smooth muscle (Mandegar et al., 2004). The cellular processes responsible for the muscularization of this distal part of the PA are not clear, but these observations suggest a central role for PASMCs in the development of PAH.
MicroRNAs (miRNAs) are a class of small, endogenous and non-coding RNAs able to negatively regulate gene expression by targeting specific messenger RNAs (mRNAs) and inducing their degradation or translational repression (Ambros, 2004; Bartel, 2009). A recent study has defined mRNA degradation as the predominant mechanistic effect of miRNA:mRNA targets (Guo et al., 2010). Several recent studies have assessed the direct role of miRNAs in vascular inflammation and in the development of vascular pathologies (Kartha and Subramanian, 2010; Urbich et al., 2008). In a recent study, miR-145 was shown to be abundantly expressed in the vessel wall (Cheng et al., 2009). MiR-145 is transcribed as a long pri-miRNA encoding both miR-143 and miR-145 on human chromosome 5 (Lio et al., 2010) and on mouse chromosome 18, regulated by a conserved SRF-binding site (Xin et al., 2009). Localization of miR-145 to the vessel wall demonstrated high expression in the smooth muscle layer in comparison with adventitial fibroblasts and endothelial cells (Cheng et al., 2009). For this reason, miR-145 is considered a smooth muscle cell phenotypic marker and modulator, able to regulate smooth muscle cell (SMC) maturation and proliferation, and vascular neointimal lesion formation through its target gene KLF-5 and its downstream signaling molecule, myocardin (Cheng et al., 2009; Elia et al., 2009). Agonists within the TGF-β superfamily have been shown to active miR-143/145 cluster via a Smad-dependent pathway (Davis-Dusenbery et al., 2011; Long et al., 2011). Moreover the analysis of miR-145, miR-143 and miR-143/145 knock-out (ko, −/−) mice showed a noticeably thinner smooth muscle layer of the aorta and other peripheral arteries, due to a reduced SMC size induced by a disruption of actin filaments Elia et al., 2009. This leads to moderate systemic hypotension and the absence of neointima formation in response to injury in miR-145 −/− mice (Xin et al., 2009). Moreover, vascular smooth muscle cells (VSMCs) isolated from single and double ko animals showed hyperproliferative activity and a higher ability to migrate towards platelet-derived growth factor (PDGF), a known chemoattractant for VSMCs (Elia et al., 2009; Xin et al., 2009). Furthermore, a pharmacological analysis of the vasculature of miR-143(145) ko mice revealed a blunted response to vasopressive stimuli (Elia et al., 2009; Xin et al., 2009). Taking together, these findings show a dedifferentiated phenotype of VSMCs in miR-145 ko and miR-143/145 double ko mice.
Despite an improved understanding of the underlying genetics, PAH remains a severe and often fatal disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes the pathology. Current treatments for PAH fail to adequately address smooth muscle proliferation that underlies PAH pathology. Thus, there is a need in the art for the development of novel therapies for PAH. MicroRNAs, which have been reported to play a role in vascular remodeling, represent a potential novel therapeutic target the development of effective treatments for PAH.